A stereoselective synthesis of (-)-viridiofungin A utilizing a TiCl 4-promoted asymmetric multicomponent reaction

Article abstract of DOI:10.1021/ol203093g

A stereoselective synthesis of (-)-viridiofungin A is described. The convergent synthesis utilized a unique highly diastereoselective multicomponent reaction between optically active phenyldihydrofuran and an α-ketoester to provide two chiral centers incl

Full text of DOI:10.1021/ol203093g

ORGANIC
LETTERS
2012
Vol. 14, No. 2
510–512
A Stereoselective Synthesis of
(À)-Viridiofungin A Utilizing a
TiCl4-Promoted Asymmetric
Multicomponent Reaction
Arun K. Ghosh* and Jorden Kass
Department of Chemistry and Department of Medicinal Chemistry, Purdue University,
560 Oval Drive, West Lafayette, Indiana 47907, United States
akghosh@purdue.edu
Received November 18, 2011
ABSTRACT
A stereoselective synthesis of (À)-viridiofungin A is described. The convergent synthesis utilized a unique highly diastereoselective
multicomponent reaction between optically active phenyldihydrofuran and an R-ketoester to provide two chiral centers including a
quarternary carbon center in a single step. Other key steps include an acyloxycarbonium ion-mediated tetrahydrofuran ring-opening reaction
and a JuliaÀKocienski olefination.
Viridiofungins were first isolated by Harris and co-workers
in 1993 from the fungus, Trichoderma viride.1 This family of
alkyl citrates exhibited a broad spectrum of antifungal
properties with minimum fungicidal concentrations in the
range of 1À20 μg/mL against a number of species. Further-
more, viridiofungins inhibited rat and yeast squalene synthe-
sis with IC50 values of 0.4À15 μM.2 This antifungal activity is
unrelated to the inhibition of ergosterol biosynthesis. In-
stead, viridiofungins showed very potent nanomolar inhibi-
tory activity against serine palmitoyltransferase, the first
enzyme in the sphingolipid biosynthesis which is responsible
for viridiofungin’s antifungal properties.3 Sphingolipids are
abundant membrane lipids important for cell recognition
and signal transduction. Due to the ability of sphingolipids
to form so-called lipid rafts, inhibition of serine palmitoyl-
transferase has been recognized as a possible target for the
treatment of hepatitis C.4 There are some indications that
viridiofungin analogs could inhibit farnesyltransferase,
which might lead to viridiofungin-based compounds with
anticancer activity.5
The initial structural assignment of the viridiofungins
was carried out by chemical degradation and spectro-
scopic studies.1 The relative and absolute stereochemistry
of viridiofungin A (1) was assigned by Hatakeyama and
co-workers through their first total synthesis in 27 steps.6
Several other synthetic studies led to the synthesis of ester
derivatives of viridiofungins. Hiersemann and co-workers7
and Barrett and co-workers8 have reported the synthesis of
viridiofungin ester derivatives. Hatakeyama and co-workers
have reported a second generation synthesis of viridiofungin
(4) Umehara, T.; Sudoh, M.; Yasui, F.; Matsuda, C.; Hayashi, Y.;
Chayama, K.; Kohara, M. Biochem. Biophys. Res. Commun. 2006, 346,
67–73.
(5) Wittinghofer, A.; Waldmann, H. Angew. Chem., Int. Ed. 2000, 39,
4192–4214.
(1) Harris, G. H.; Jones, E. T. T.; Meinz, M. S.; Nallin-Omstead, M.;
Helms, G. L.; Bills, G. F.; Zink, D.; Wilson, K. E. Tetrahedron Lett.
1993, 34, 5235–5238.
(6) Esumi, T.; Iwabuchi, Y.; Irie, H.; Hatakeyama, H. Tetrahedron
Lett. 1998, 39, 877–880.
(2) Onishi, J. C.; Milligan, J. A.; Basilio, A.; Bergstrom, J.; Curotto,
J.; Huang, L.; Meinz, M.; Nallin-Omstead, M.; Pelaez, F.; Rew, D.;
Salvatore, M.; Thompson, J.; Vicente, F.; Kurtz, M. B. J. Antibiot. 1997,
50, 334–338.
(3) Mandala, S. M.; Thornton, R. A.; Frommer, B. R.; Dreikorn, S.;
Kurtz, M. B. J. Antibiot. 1997, 50, 339–343.
€
(7) Pollex, A.; Millet, A.; Muller, J.; Hiersemann, M.; Abraham, L.
J. Org. Chem. 2005, 70, 5579–5591.
(8) Goldup, S. M.; Pilkington, C. J.; White, A. J. P.; Burton, A.;
Barrett, A. G. M. J. Org. Chem. 2006, 71, 6185–6191.
r
10.1021/ol203093g
Published on Web 12/23/2011
2011 American Chemical Society

A in 22 steps.9 Herein we report an asymmetric synthesis of
viridiofungin A which can be utilized for analog preparation.
Our synthetic strategy to viridiofungin A is shown in
Figure 1. Strategic bond disconnections provided funtio-
Scheme 1. Multicomponent Reaction
active phenyldihydrofuran 7,11 R-ketoester 8,12 and triethyl
silane (Scheme 1). The reaction involved TiCl4-promoted
activation of the R-ketoester followed by attack of phenyldi-
hydrofuran, presumably anti to the phenyl group forming an
oxocarbenium ion. Subsequent reaction of this presumed
oxocarbenium ion with a hydride from triethylsilane formed
two adjacent chiral centers including a quarternary car-
bon center diastereoselectively. This reaction proceeded
with good yield and an excellent diastereomeric ratio
(dr > 20:1). The stereochemical outcome can be rationa-
lized based upon product-like transition-state models 9a
and 9b. Presumably, the model 9b is preferred, as the
developing nonbonded interactions are less for an exo-
oriented bulky five-membered Ti-chelate compared to an
endo-oriented Ti-chelate in 9a. Similar transition-state
models were proposed by us previously.10d
The acetylene functionality in 6 was converted to the
corresponding carboxylic acid via hydroboration with
boraneÀTHF complex followed by oxidation with alka-
line hydrogen peroxide.13 The ethyl ester was subse-
quently hydrolyzed with aqueous lithium hydroxide to
provide the corresponding diacid. This diacid was con-
verted to the di-tert-butyl ester 10 by treatment with N,
N-diisopropyl-O-2-tert-butylisourea in CH2Cl2. The tert-
butyl ester is necessary due to base incompatibility at later
stages of the synthesis.7
Figure 1. Retrosynthetic analysis.
nalized aldehyde 2, sulfone 3, and tyrosine derivative 4.
A JuliaÀKocienski olefination of 2 with 3 is planned to
provide the trans-olefin in 1. This side chain attachment
was previously explored by Hiersemann and co-workers.7
The highly functionalized aldehyde could be derived from
the oxidative cleavage of styrene derivative 5, which in
turn could be obtained from a ring-opening reaction of the
corresponding functionalized tetrahydrofuran derivative of
6. The key intermediate would be synthesized by an asym-
metric multicomponent reaction of optically active phenyl-
dihydrofuran 7and an appropriately functionalized ketoester.
Such asymmetric multicomponent reactions and acyloxycar-
bonium ion mediated opening of tetrahydrofuran rings were
developed previously in our laboratory.10,11
The synthesis begins with the titanium tetrachloride
mediated multicomponent reaction between optically
With the synthesis of requisite tetrahydrofuran 10, we
then explored the ring-opening reaction. Previously, we
carried out similar ring-opening reactions using a catalyt-
ic amount of ZnCl2 in the presence of acetic anhydride.11
However, subjecting 10 to these conditions led to un-
wanted side reactions. After surveying a number of Lewis
(9) Morokuma, K.; Takahashi, K.; Ishihara, J.; Hatakeyama, S.
Chem. Commun. 2005, 41, 2265–2267.
(10) (a) Ghosh, A. K.; Kass, J. Chem. Commun. 2010, 46, 1218–1220.
(b) Ghosh, A. K.; Kulkarni, S.; Xu, C. -X.; Fanwick, P. B. Org. Lett.
2006, 8, 4509–4511. (c) Ghosh, A. K.; Xu, C.-X.; Kulkarni, S. S.; Wink,
D. Org. Lett. 2005, 7, 7–10. (d) Ghosh, A. K.; Kawahama, R.; Wink, D.
Tetrahedron Lett. 2000, 41, 8425–8429. (e) Ghosh, A. K.; Kawahama, R.
Tetrahedron Lett. 1999, 40, 1083–1086.
(12) Guo, M.; Li, D.; Zhang, Z. J. Org. Chem. 2003, 68, 10172–10174.
(13) Zweifel, G.; Backlund, S. J. J. Am. Chem. Soc. 1977, 99, 3184–
3185.
(11) (a) Ghosh, A. K.; Kulkarni, S. S.; Xu, C. -X.; Shurrush, K.
Tetrahedron: Asymmetry 2008, 19, 1020–1026. (b) Ghosh, A. K.;
Shurrush, K.; Kulkarni, S. J. Org. Chem. 2009, 74, 4508–4518.
Org. Lett., Vol. 14, No. 2, 2012
511

were necessary. Standard conditions for acetate hydro-
lysis such as K2CO3 in methanol resulted in elimination
rather than deprotection. To circumvent this problem,
diacetate 5 was treated with allyl magnesium bromide at
À78 °C to give the diol. The primary alcohol was pro-
tected as its tert-butyldimethylsilyl ether with TBSOTf
and 2,6-lutidine at À78 °C. Subsequent protection of the
tertiary alcohol as its triethylsilyl ether provided styrene
derivative 12.
Scheme 2. Tetrahydrofuran Ring Opening
Oxidative cleavage of styrene 12 with ozone followed
by reductive workup afforded the corresponding alde-
hyde (Scheme 3). This aldehyde was subjected to
JuliaÀKocienski olefination with known sulfone 3.7 Thus,
treatment of sulfone 3 with KHMDS in THF at À78 °C
followed by addition of the aldehyde via cannula afforded
the alkene 13 as a single trans-stereoisomer. Removal of
the silyl protecting groups with HF-pyridine followed by
oxidation of the primary alcohol using Jones’ reagent
afforded the acid 14 with concomitant deprotection of
the dioxolane protecting group.
Scheme 3. Completion of Viridiofungin A
To complete the synthesis of viridiofungin A, coupling
of acid 14 with tyrosine tert-butyl ester 4 was carried out
by utilizing EDCI hydrochloride, N-methylmorpholine,
and hydroxybenzotriazole in DMF to provide tri-tert-
butyl ester 15. While deprotection of tri-tert-butyl ester 15
is known from the second generation synthesis by
Hatakeyama,9 commercial grade (88%) formic acid
gave incomplete conversion to (À)-viridiofungin A and
instead gave a mixture of mono- and di-tert-butyl esters.
However, when 96% formic acid was used, removal of all
three tert-butyl esters was accomplished in 1 h. As such,
deprotection of the tert-butyl esters by treatment with
neat 96% formic acid at 23 °C for 1 h furnished synthetic
(À)-viridiofungin A (1, [R]23 À11.0 (c 0.39, MeOH)).
D
The spectral data (1H and 13C NMR) of synthetic
(À)-viridiofungin A are identical with those reported for
the natural (À)-viridiofungin A.1
In summary, we have achieved a stereoselective synthe-
sis of (À)-viridiofungin A (1). The convergent synthesis
features a highly diastereoselective multicomponent re-
action to form two key stereocenters including a quatern-
ary stereocenter in high yield. Both stereogenic centers are
derived from (S)-2-phenyl-2,3-dihydrofuran. The synthe-
sis will provide a convenient access to a variety of
viridiofungin derivatives.
acids, we found that exposure of 10 to a catalytic amount of
Cu(OTf)2 (20 mol %) and acetic anhydride in refluxing
toluene smoothly gave rise to a ring opened product
through a presumed acyloxycarbonium ion intermediate
followed by an unexpected collapse of the di-tert-butyl esters
to provide anhydride 11 in near-quantitative yield (Scheme 2).
Basic hydrolysis conditions only provided the elimina-
tion product. However, treatment with aqueous acetic
acid in THF resulted in anhydride opening to the corre-
sponding diacid. The resultant diacid was esterified by treat-
ment with N,N-diisopropyl-O-2-tert-butylisourea in CH2Cl2
to give di-tert-butyl ester 5. For the subsequent JuliaÀ
Kocienski olefination,14 protecting group manipulations
Acknowledgment. Financial support of this work was
provided by the National Institutes of Health (in part) and
Purdue Research Foundation (fellowship to J.K.). We
would like to thank Dr. Jun Takayama (Purdue University)
for preliminary investigation of asymmetric multicompo-
nent reactions.
Supporting Information Available. Experimental pro-
cedures and 1H and 13C NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26–28.
512
Org. Lett., Vol. 14, No. 2, 2012